Recipient, Nobel Prize in Physiology or Medicine, 2002; Professor of Biochemistry and Molecular Biophysics, Columbia University; Author, The Age of Insight; In Search of Memory

BIOLOGICAL MARKERS FOR MENTAL ILLNESS

Biology in general and the biology of mind in particular have become powerful scientific disciplines. But a major lack in the current science of mind is a satisfactory understanding of the biological basis of almost any mental illness. Achieving a biological understanding of schizophrenia, manic-depressive illness, unipolar depression, anxiety states, or obsessional disorders would be a paradigm shift for the biology of mind. It would not only inform us about some of the most devastating diseases of humankind, but since these are diseases of thought and feeling, understanding them would also tell us more about who we are and how we function.

To illustrate the embarrassing lack of science in this area, let me put this problem into a historical perspective with two personal introductory comments.

First, in the 1960s, when I was a psychiatric resident at the Massachusetts Mental Health Center, of the Harvard Medical School, most psychiatrists thought that the social determinants of behavior were completely independent of the biological determinants and that each acted on different aspects of mind. Psychiatric illnesses were classified into two major groups — organic mental illnesses and functional mental illnesses — based on presumed differences in origin. That classification, which dated to the nineteenth century, emerged from postmortem examinations of the brains of mental patients.

The methods available for examining the brain at that time were too limited to detect subtle anatomical changes. As a result, only mental disorders that entailed significant loss of nerve cells and brain tissue such as Alzheimer's disease, Huntington's disease, and chronic alcoholism were classified as organic diseases, based on biology. Schizophrenia, the various forms of depression, and the anxiety states produced no readily detectable loss of nerve cells or other obvious changes in brain anatomy and therefore were classified as functional, or not based on biology. Often, a special social stigma was attached to the so-called functional mental illnesses because they were said to be "all in a patient's mind." This notion was accompanied by the suggestion that the illness may have been put into the patient's mind by his or her parents.

With the passage of forty years we have made progress and the advent of a paradigm shift for the science of the mind. We no longer think that only certain diseases affect mental states through biological changes in the brain. Indeed, the underlying precept of the new science of mind is that all mental processes are biological — they all depend on organic molecules and cellular processes that occur literally "in our heads." Therefore, any disorder or alteration of those processes must also have a biological basis.

Second, in 2001 Max Cowan and I were asked to write a review for the Journal of the American Medical Association about molecular biological contributions to neurology and. In writing the review, we were struck by the radical way in which molecular genetics had transformed neurology. This led me to wonder why molecular biology has not had a similar transformative effect on psychiatry.

The fundamental reason is that neurological diseases and psychiatric diseases differ in several four important ways.

Neurology has long been based on the knowledge of where in the brain specific diseases are located. The diseases that form the central concern of neurology — strokes, tumors, and degenerative diseases of the brain — produce clearly discernible structural damage. Studies of those disorders taught us that, in neurology, location is key. We have known for almost a century that Huntington's disease is a disorder of the caudate nucleus of the brain, Parkinson's disease is a disorder of the substantia nigra, and amyotrophic lateral sclerosis (ALS) is a disorder of motor neurons. We know that each of these diseases produces its distinctive disturbances of movement because each involves a different component of the motor system.

In addition, a number of common neurological illnesses, such as Huntington's, the fragile X form of mental retardation, some forms of ALS, and the early-onset form of Alzheimer's, were found to be inherited in a relatively straightforward way, implying that each of these diseases is caused by a single defective gene.

Pinpointing the genes and defining the mutation that produce these diseases therefore has been relatively easy.

Once a mutation is identified, it becomes possible to express the mutant gene in mice and flies and thus to discover its mechanism of pathenogenesis: how the gene gives rise to disease.

Over the last 20 years neurology has been revolutionized by the advent of molecular genetics. As a result of knowing the anatomical location, the identity, and the mechanism of action of specific genes, diagnoses of neurological disorders are no longer based solely on behavioral symptoms. We have even established new diagnostic categories with the neurological diseases such as the ion channellopathies, such as familial periodic paralysis, characterized by aberrant function of ion channel proteins, and thetrinucleotide repeat disorders such as Huntington Disease and Fragile-X syndrome, where there is an abnormal and unstable replication of short repeating elements in DNA that alter the function of the resulting protein.

These new diagnostic categories are based not on symptomatology but on the dysfunction of specific genes, proteins, neuronal organelles, or neuronal systems. Moreover, molecular genetics has given us insight into the mechanisms of pathogenesis of neurological disease that did not exist 20 years ago. Thus in addition to examining patients in the office, physicians can order tests for the dysfunction of specific genes, proteins, and nerve cell components, and they can examine brain scans to see how specific regions have been affected by a disorder.

By contrast to the brilliant impact on neurology, molecular genetics has so far had only a minor impact on psychiatry. We may well ask: Why is that so?

Tracing the causes of mental illness is a much more difficult task than locating structural damage in the brain. The same four factors that have proven useful in studying neurological illnesses have been limiting in the study of mental illness.

A century of postmortem studies of the brains of mentally ill persons failed to reveal the clear, localized lesions seen in neurological illness. Moreover, psychiatric illnesses are disturbances of higher mental function. The anxiety states and the various forms of depression are disorders of emotion, whereas schizophrenia is a disorder of thought. Emotion and thinking are complex mental processes mediated by complex neural circuitry. Until quite recently, little was known about the neural circuits involved in normal thought and emotion.

Furthermore, although most mental illnesses have an important genetic component, they do not have straightforward inheritance patterns, because they are not caused by mutations of a single gene. Thus, there is no single gene for schizophrenia, just as there is no single gene for anxiety disorders, depression, or most other mental illnesses. Instead, the genetic components of these diseases are thought to arise from interaction with the environment of several genes, each of which exerts a relatively small effect. Together, the several genes create a genetic predisposition — a potential — for a disorder. Most psychiatric disorders are caused by a combination of these genetic predispositions and some additional, environmental factors. For example, identical twins have identical genes. If one twin has Huntington's disease, so will the other. But if one twin has schizophrenia, the other has only a 50 percent chance of developing the disease. To trigger schizophrenia, some other, nongenetic factors in early life — such as intrauterine infection, malnutrition, stress, or the sperm of an elderly father — are required. Because of this complexity in the pattern of inheritance, we have not yet identified most of the genes involved in the major mental illnesses.

As a result we know little about the specific genes involved in any major mental illness.

Because of points two and three, we have no satisfactory animal models for most mental disorders.

What is then needed to achieve a better biological understanding of mental illness?

Two initial requirements are essential and, in principle, obtainable within the next two decades:

We need biological markers for mental illness so that we could understand the anatomical basis of these diseases and diagnose them objectively and follow their response to treatment. A beginning is evident here is the case of depression which is associated with hyperactivity in the prefrontal cortical area, Broadmann Area 25 in anxiety states where there is hyperactivity in the amygdala, and in obsessive compulsive neurosis where there is an abnormality in the striatum.

We need identification of the genes for various mental illnesses, so that we can understand the molecular basis of these diseases.

These two advances would enhance our ability to understand these disorders better and recognize them earlier. But in addition, these advances would open up completely new approaches to the treatment of mental illness, an area that has been at a pharmacological standstill for depression, bipolar disorders, and schizophrenia for the last twenty years.